We review the history and pathophysiology of neonatal jaundice. We are joined by Jessica Morse, MD, Assistant Professor of Neonatal-Perinatal Medicine at the University of Texas Southwestern Medical Center, and Medical Director of the Parkland Memorial Hospital Newborn Nursery.
Dr. Neeta Goli:
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern Newborn Nursery.
Dr. Neeta Goli:
Welcome back to the podcast. In today's episode, we'll discuss a common concern in the newborn nursery, jaundice, also known as hyperbilirubinemia. We're joined today by Dr. Jessica Morse, who's the Medical Director of the Parkland Newborn Nursery and a proud mom of two.
Dr. Neeta Goli:
Dr. Morse, thanks so much for joining us today.
Dr. Jessica Morse:
Thank you so much for having me.
Dr. Neeta Goli:
Jaundice is one of the things we keep close track of in the newborn nursery, so we thought it's important for all our listeners to understand it well. It's actually so important and there's so much to talk about that we broke it up into two episodes. So today we'll be discussing the history and pathophysiology of jaundice. Our next episode, we'll address the clinical approach and management.
Dr. Neeta Goli:
Dr. Morse, to start off with, please can you tell us a little bit about the history of jaundice and why we pay attention to it?
Dr. Jessica Morse:
So, as everybody knows, hyperbilirubinemia, or jaundice, is caused by an elevated level of bilirubin in the blood. Bilirubin is a byproduct of hemoglobin breakdown from red blood cells. So when red cells break down, it causes hemoglobin that then builds up in the blood leading to what we call hyperbilirubinemia. The reason why we worry about hyperbilirubinemia in our neonates is that we know that high levels can accumulate in the basal ganglia, which leads to what we call bilirubin encephalopathy in the acute phase. And the chronic phase is known as kernicterus, and that's probably the more familiar term that everybody knows about.
Dr. Jessica Morse:
We know that historically, before the 1950s, kernicterus was very, very common, and there were high rates of it. And this was most likely due to Rh incompatibility or Rh hemolytic disease of the neonate. But now with appropriate management, we're able to actually prevent this Rh hemolytic disease of a neonate, as well as we're able to treat high levels of hyperbilirubinemia before it leads to this bilirubin encephalopathy.
Dr. Neeta Goli:
And stay tuned. We'll get into a little bit more detail about the Rh incompatibility later in this episode. But first, can you tell us a little bit about the natural history of jaundice in neonates?
Dr. Jessica Morse:
Every neonate has some small level of jaundice. About two-thirds of the neonates will have a little bit more level, and then a small percentage of that will go on to what we call pathologic jaundice or actual need to where we need to intervene to treat their level of jaundice. We typically know that the bilirubin slowly rises in the first few days. It'll peak about three to five days of life and then slowly decrease over the next two weeks of life.
Dr. Neeta Goli:
So when should I be worried if a baby's jaundiced?
Dr. Jessica Morse:
We know that red flags are when significant jaundice develops in the first 24 hours of life. We always say that jaundice in the first 24 hours of life is pathologic. It's not normal if there is a conjugated or direct hyperbilirubinemia, or if you notice that the baby is jaundiced at over two weeks of age.
Dr. Neeta Goli:
Okay. So now that we understand a little bit more about the history of jaundice, let's get into the pathophysiology of it. Dr. Morse, I know when you teach med students about jaundice, you like to organize it into two classes, unconjugated or indirect, versus conjugated or direct hyperbilirubinemia. So let's talk about the conjugated hyperbilirubinemia first. Can you walk me through what can cause this?
Dr. Jessica Morse:
Yeah. A conjugated or a direct hyperbilirubinemia is actually very rare in our neonates. We typically don't see this very often, and when we do it's often very concerning. So something to note, whenever you do have a baby that has a significant hyperbilirubinemia, it is really important that you get not only a total bilirubin, but you also get a direct bilirubin. That way you can establish whether or not this is an unconjugated versus a conjugated hyperbilirubinemia, and also to get a nice baseline of that direct bilirubin should we need to monitor that in the future. We do know that bili abnormal levels vary from institution to institution. So you should make sure that you check what your institution's normal levels for a neonate are, and it can vary from lab to lab.
Dr. Neeta Goli:
So can a conjugated or direct hyperbilirubinemia ever be physiologic or normal?
Dr. Jessica Morse:
No, it is never normal. And so with that, we know that it's very important to understand, when we care for these babies, what we need to be thinking about when you discover a direct hyperbilirubinemia. I think the most common thing that everybody tends to think of when they notice a direct hyperbilirubinemia or what they worry about when you notice that your infant has a direct hyperbilirubinemia is you worry about something called biliary atresia, or more commonly, an obstruction somewhere in that biliary tree. It could be caused by a stenosis, but again, the big thing that everybody worries about is atresia when the biliary tree is atretic.
Dr. Jessica Morse:
Usually, we don't actually notice that our babies have a direct hyperbilirubinemia in the immediate postnatal period. Usually what happens is the direct bili is going to rise over time. Again, that's really why it's important to get that baseline direct bili whenever you are looking at a baby with hyperbilirubinemia. And so, usually we know that the earlier we can diagnose biliary atresia, the better. If biliary atresia is left to its own devices, it definitely leads to liver disease, and eventually most of those neonates need a liver transplant. We do know that better outcomes occur if we can do the Kasai procedure by at least seven weeks of age.
Dr. Jessica Morse:
Some other causes of a direct hyperbilirubinemia very less common are other genetic causes that can lead to obstruction, such as Dubin-Johnson or Rotor syndrome. And it's also important to note that there are some metabolic causes of a direct hyperbilirubinemia. Hypothyroidism, which can cause actually a direct or indirect, we think maybe leads to cholestasis, but the mechanism of which it causes this is really unclear. And then galactosemia, again, it's also important to note that that can be a direct or indirect hyperbilirubinemia. Again, for galactosemia the cause of how it leads to this is a little bit unclear, but it's thought to be maybe due to conjugation that's inhibited by the metabolites. Again, very unclear as to how it leads to this, but something to be aware of.
Dr. Jessica Morse:
And then, the last thing that you need to be aware of if you notice a direct hyperbilirubinemia in your neonate is that sepsis can also lead to this. So making sure that your baby is appearing well, has normal vital signs, and then a CBC is within normal. Also of note, CMV can also lead to a direct hyperbilirubinemia, and the mechanism by which that CMV can cause this is unclear.
Dr. Neeta Goli:
That was a pretty thorough explanation of conjugated or direct hyperbilirubinemia. So let's move on to indirect or unconjugated. There are some times when this can be physiologic and sometimes it can be pathologic. Let's talk more about the physiologic causes of unconjugated hyperbilirubinemia.
Dr. Jessica Morse:
So, if everyone remembers, when babies are in the womb, they are in a very low oxygen environment. We all know that as blood flows through the mom, the mom takes out all the oxygen that she needs first, and then whatever's left over get passed to baby. Because of this, our fetus has to have mechanisms by which to get as much oxygen out of the blood as possible. To do this, babies have something called fetal hemoglobin, which has a higher affinity for oxygen. It binds oxygen more readily so that it can leach out as much oxygen as possible, and then they also have more of it. So their hematocrits tend to be on the higher side in the fifties to sixties, whereas you or I would have a hematocrit usually in the twenties to thirties. And also another thing, if you have more red blood cells total, then they break down. Then, obviously, you'll have more that gets broken down, which again, when red blood cells get broken down, it leads to increased levels of bilirubin.
Dr. Jessica Morse:
One of the other things that leads to physiologic jaundice is that infants have a very immature liver. There is an increased reabsorption of bilirubin due to the decreased activity of the UDP-glucuronosyltransferase enzyme activity. In other words, the babies, instead of excreting the bilirubin, they actually kind of hold onto it and it kind of gives this increased enterohepatic circulation of the bilirubin. And so, obviously, if you can't excrete it, the levels are going to continue to rise as more and more red blood cells get broken down.
Dr. Neeta Goli:
In addition to regular physiologic jaundice, there are some causes that aren't necessarily pathologic, but aren't necessarily the typical physiologic jaundice. Can you talk a little bit more about this?
Dr. Jessica Morse:
Absolutely. This usually has to do with the way that babies eat, more specifically in breastfed babies. There's something called breastfeeding jaundice, or as I like to refer to it as inadequate feeding jaundice. As you know, bilirubin is excreted in infant stool, and if you are not taking enough in, then you can't really make enough stool for you to excrete the bilirubin. And why this occurs more specifically in breastfed infants is that in the early days, mom produces something called colostrum. It's different than that mature milk that comes in, in a few days, and what we think of it when we say to our med students or when we ask our moms, "Has your milk come in yet?" That's what we're referring to.
Dr. Jessica Morse:
And so the colostrum is often a smaller quantity. It's not as much volume. It does contain all of the nutrients, calories, things the infants need to grow and thrive in the first couple of days of life. However, the volume is not a lot. If they don't have a lot of volume, they don't make a lot of stool, and so they can't excrete out the bilirubin in their stool. And so they tend to hold onto it longer, again, leading to what we call a breastfeeding jaundice or an inadequate feeding jaundice.
Dr. Jessica Morse:
The other thing that is related to feeding, or breast milk specifically, is something called breast milk jaundice. This is where we think there is an enzyme in the breast milk, although it's not really fully fleshed out, that causes, again, this enterohepatic circulation of the bilirubin. In other words, it doesn't get really excreted out. It kind of stays in the baby's system. And this jaundice, typically we see around the 9 to 10 days of life or so. Usually, these babies will come into clinic for a follow-up visit. They'll be gaining weight. They'll be eating well. They'll be having adequate stools, adequate voids, but the mom just notices that the baby is persistently jaundice.
Dr. Jessica Morse:
They'll check out bilirubin level. It's usually in the 9 or 10 range, not enough to need to do anything to treat the jaundice. It just persists. Eventually, this will go away. It's just going to take a little bit longer for it to go away, and usually you don't need to change the baby to formula or add in formula. You don't need to add water or anything like that into their diet. You just want to feed through and tell the mom to continue to breastfeed like she has been, and eventually it will go away. So a lot of reassurance for the families at that point.
Dr. Neeta Goli:
Okay. That was a great explanation for our listeners. So now that we understand why you might have normal unconjugated jaundice, let's talk about pathologic causes of unconjugated hyperbilirubinemia in our neonates.
Dr. Jessica Morse:
Whenever I think of a pathologic cause, the first thing that comes to mind is hemolysis. The two biggest things of hemolysis that we worry about is number one, Rh incompatibility, and then the other thing would be ABO incompatibility. With Rh incompatibility, usually you have a mom that has Rh-negative blood type and an infant that is Rh-positive. Somehow during the first pregnancy, whether it be early on in the pregnancy or at the birthing process, mom becomes isoimmunized. In other words, she develops antibodies against that Rh-positive antigen, or anti-D antibodies against baby's blood type. And so what happens then is these antibodies attack baby's red blood cells and cause them to break down, increasing the levels of bilirubin.
Dr. Jessica Morse:
This typically becomes a problem in utero because these antibodies are IgG, so therefore they cross the placenta. So these babies typically are very, very ill whenever they are delivered and typically will end up in the NICU. These are not our typical normal neonates that we will see in the newborn nursery. And oftentimes, yes, they will be jaundiced at birth, but really what causes the most problems is when it begins in utero. What happens is these red blood cells get broken down in the baby when they're inside mom. Usually, the bilirubin is not a problem because the mom's body actually will filter out that bilirubin. But it's the anemia that is causes from the significant hemolysis that occurs, and this can lead to something called hydrops or hydrops fetalis.
Dr. Jessica Morse:
There are ways that we can treat this. Number one is we give moms something called RhoGAM. Usually, it's given to moms at 28 weeks and after delivery and then anytime she bleeds during a pregnancy. Why we typically don't see this nowadays is because of RhoGAM. It helps to prevent mom from creating these antibodies. However, we still do see it because oftentimes moms can become pregnant, not know that they're pregnant and miscarry early on and become isoimmunized at that point. Typically, we do not see Rh incompatibility in our infants until it's at a subsequent pregnancy. So, usually not seen with first but subsequent pregnancies.
Dr. Jessica Morse:
So now on to our ABO incompatibility. ABO incompatibility is most commonly seen when mom has type O blood and baby has type A, B or AB blood type. Usually, moms do have type O blood have these naturally occurring IgG antibodies that are anti-A and anti-B. But not all moms who are a type O blood have these IgG antibodies, and it's unclear most of the time which moms do have these antibodies and which moms don't. These antibodies then, since they are IgG, will cross the placenta and into baby, so that when the babies are born they can develop a significant hyperbilirubinemia that will need to be treated.
Dr. Jessica Morse:
It's not as significant as what we see with Rh incompatibility because these IgG anti-A or anti-B antibodies enter the fetal circulation from the mom. But there are many different fetal cell types, leaving fewer antibodies available for binding onto fetal red blood cells, as well as that fetal red blood cells surface A and B antigens are not fully developed during gestation. And so there are a smaller number of antigenic sites for which this anti-A or anti-B and IgG can bind to.
Dr. Jessica Morse:
So other causes of hemolysis include any of those babies that have cephalohematomas or bruising from delivery. As you know, cephalohematomas and bruising are where blood is released. That blood has to get broken down, so it can cause a temporary increase in the bilirubin level. Another pathologic cause, as we kind of talked about earlier, is whenever you have polycythemia or an increased number of red blood cells. Again, if you have more of the red blood cells, more of them get broken down, which can cause an increase in your levels of bilirubin. We typically see polycythemia in our large for gestational age infants, our infants of diabetic mothers and occasionally in our small for gestational age infants. So it's really important that you also check hematocrit or hemoglobin on those babies.
Dr. Jessica Morse:
Some other less common cause of unconjugated hyperbilirubinemia in the infants are you can, again, see it with some metabolic causes, which we talked about earlier, such as hypothyroidism. Again, just to remind you, it can cause an either or both, an indirect or direct hyperbilirubinemia. And galactosemia, again, this can cause a direct or indirect hyperbilirubinemia.
Dr. Jessica Morse:
There can also be some genetic causes. Again, these are very, very rare, and typically not seen, but again, to keep in the back of your mind, especially when you have a neonate that has a significant hyperbilirubinemia that you don't have a really good explanation for. These can be Gilbert or Crigler-Najjar. And then, again, you can also see some increase in your bilirubin levels with G6PD syndrome, and then some other genetic causes that can lead to hemolysis include G6PD and hereditary spherocytosis. Both of these can lead to an increase in your bilirubin as those red blood cells are broken down. Again, these are more rare causes of a hyperbilirubinemia in a neonate.
Dr. Jessica Morse:
Of note, you typically will not see a significant increase in your bilirubin with infants that have sickle cell or hemoglobin SC disease. This is due to the fact that they have fetal hemoglobin and this disease only affects adult hemoglobin. There can also be iatrogenic causes, including some medications that you give, more specifically, ceftriaxone, which we do have to give occasionally to our neonates, but something that you need to keep in the back of your mind as you prescribe these medications. And then, obviously, you must always keep in the back of your mind, sepsis. So again, making sure that the neonate is well appearing with good vital signs.
Dr. Neeta Goli:
Okay. Thanks so much for the really educational and thorough discussion. For our listeners, now that you understand why babies get jaundice, make sure to stay tuned to our next episode so you can hear more about what to do about it.
Dr. Neeta Goli:
Dr. Morse, thanks for joining us today. To end the episode, do you have any tips for success for our listeners while they're taking care of newborns?
Dr. Jessica Morse:
Newborns are a lot of fun and they typically are well until they're not, so make sure that you pay close attention whenever you are examining them.
Dr. Neeta Goli:
Great advice. Thanks so much for joining us today, Dr. Morse.
Dr. Jessica Morse:
Thanks for having me.
Dr. Neeta Goli:
Thanks for listening to newborn news. We hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback, or suggestions for future episodes, please email me at NewbornNews@utsouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests and do not necessarily reflect the views of the university.